Doctors have long been using organ and tissue transplantation to treat certain medial conditions. One example of tissue transplants is corneal tissue allografts. Corneal tissue allografts have been successfully conducted since 1905. Today, corneal tissue transplantation is used to treat poor vision due to corneal perforation, infection, scarred tissue as well as complications from cataract surgery and other medical conditions. There are two basic categories of corneal tissue transplants, those that require endothelial cells and those that do not. The corneal endothelium is a thin cell layer on the posterior surface of the cornea. This layer allows transport of solutes and nutrients of the aqueous humor into the cornea while pumping water out of the stroma to the aqueous humor. As a result of such functioning, it follows that one of the primary outcomes of a properly functioning endothelial cell layer is the maintenance of a clear cornea. The present invention discloses a novel and more cost-effective manner through which a substantially similar result (i.e. a clear cornea) is achievable without requiring the transplantation, preservation, or storage of actual endothelial cells.
Some medical conditions, including those where the endothelium is diseased or damaged, require that a viable endothelial layer be transplanted as well as the rest of the corneal tissue. There are situations, however, where the patient's endothelial layer may remain intact and only a portion of the corneal tissue allograft is necessary. Some examples include corneal scars, certain corneal dystrophies, ocular surface deficiencies, chemical or surgical burns and keratoconus. Based on information reported by the Eye Bank Association of America in its 2012 EBAA Annual Statistics Report, about 20% of over 68,000 corneal tissues provided for transplantation from its member eye banks use corneal tissues without the endothelium. In addition, there are some other ocular procedures where a structural or tectonic graft is necessary such as corneal perforations and pterygiums where corneal tissue material is used to patch a patient's compromised surface tissue.
Traditional corneal tissue processing methods seek to preserve the donor corneal tissue by using an organ culture based media in combination with other additives and antibiotics. These corneal tissue storage media, principally Optisol GS (Bausch & Lomb, Costa Mesa, Calif.), can maintain corneal tissue viability for up to fourteen days in combination with refrigeration. With the passage of time, the corneal tissue becomes edematous, loses its transparency and, ultimately, becomes unsuitable for transplantation. There are some known alternatives to cold storage of corneal tissue in preservation media used for tectonic applications. Some of these methods include warm temperature organ culture media, glycerol and alcohol preservation of corneas as well as gamma irradiation. Depending on the method applied, these methods may lack adequate levels of sterility, compromise the corneal stromal matrix, compromise the corneal clarity, and compromise the corneal elasticity or some combination thereof.
One existing method for sterilizing and storing corneal tissue that does not require the endothelial layer remain intact or viable is called Visiongraft and is described in “The Intraoperative Impression and Postoperative Outcomes of Gamma Irradiated Corneas in Corneal and Glaucoma Patch Surgery” (Yassine Daoud et al., 30 CLINICAL SCIENCE 12, 1387-91 (December 2011). There are numerous problems associated with the Visiongraft process. The Visiongraft process uses plasma derived human serum albumin (pdHSA). Human plasma is a complex material composed of hundreds of biochemical entities. Albumin is the most concentrated entity (40,000 mg/liter) in human serum. Typically, pdHSA is not obtained from a single donor but generated as a pool of albumin from multiple paid donors. The ramification of this is that there exists a lot to lot variability that may affect performance. The variability is addressed by the use of recombinant albumin. Human plasma products have the ability to transmit infectious agents such as HIV, HBV, HCV, HAV, HEV, HGV, TT virus, and Parvovirus B19 [World Health Organization, WHO Recommendations for the Production, Control and Regulation of Human Plasma for Fractionation (October 2005)]. Human plasma may also contain mycoplasma and prions.
The Visiongraft process also sterilizes the cornea tissue using gamma irradiation. Gamma irradiation is typically conducted using a Cobalt 60 source. The gamma source, however, generates heat in the environment that will increase the temperature within the exposure chamber. Typically, the gamma source will be exposed to the irradiation chamber (raised out of its water environment) most of the working day, which causes a buildup of heat. Since corneal tissue may be damaged by heat and irradiation, both must be controlled and kept to a minimum.
Gamma radiation can penetrate through 2-3 inches of lead shielding. Thus, due to gamma's penetration ability products of all types are exposed to gamma rays in a 3 dimensional arrangement (containers) on conveyor belts in order to maximize throughput at the gamma facility. This use of 3 dimensional arrangements is not optimal for corneal tissue as it is difficult to obtain a uniform dose throughout the container. Gamma radiation also poses a potential risk to those workers who operate the gamma radiation facility. Overall, gamma radiation is expensive due to the necessary shielding for employees because of the deeply penetrating gamma rays, long exposure time due to the dose rate, inability to turn off the fuel rods, as well as the cost of final storage and disposition of spent fuel rods.
The Visiongraft process also requires that the corneal tissue be fully submerged in storage media in a glass vial. Fully submersing corneal tissue into media in a glass vial makes the identification of clear tissue, such as corneal tissue, significantly harder. The cost of the extra pdHSA required to fill such a prior art vial is also a concern. The corneal tissue needs to be adequately soaked to remove all residual media that may have saturated the transplant tissue. In addition, glass vials, after exposure to gamma radiation, will turn brown. This browning makes it even more difficult to view the transparent tissue inside the storage container, which will create problems in ensuring adequate quality control during tissue release and tissue location/removal at surgery. Additionally, glass vials can break or leak during transport or in hospital surgical suites during an operation, causing potential harm to both those handling the tissue as well as the tissue itself. Breakage or leakage can also lead to a delay of the surgical procedure as well as upcharges to the patient.
The danger of transferring the infectious agents (such as HIV, HBV, HCV, HAV, REV, HGV, TT virus, Parvovirus B19, mycoplasma and prions) with the donor pdHSA prompted development of rHSA (Recombinant Human Serum Albumin), which is free from the respective pathogens. Such formulations are disclosed in US 2005/0281861 A1 (Hughes et al.) in which rHSA, eye and sterilization are mentioned. However, this is a drug delivery system. The implant is an intravitreal or interocular implant and is a polymer, not a collagenous biological tissue.
The human cornea has 5 layers. Moving anterior to posterior, there exists: (1) Corneal epithelium (the outermost layer of the cornea), (2) Bowman's membrane (a membrane between the epithelium and the corneal stroma), (3) Corneal stroma (the largest/thickest layer of the cornea), (4) Descemet's membrane (membrane between the stroma and the corneal endothelium), and (5) Corneal endothelium (innermost layer of the corneal containing living endothelial cells).
Approximately 70 to 75% of corneal blindness is due to a compromised endothelial cell layer (either by disease or eye trauma). In such cases, an endothelial cell layer transplant or, more often, a posterior cornea transplant with a viable endothelium is required. Most eye bank corneal storage methods and media intend to preserve the viable endothelial cells, which are required for surgeries such as those above. In contrast to such processes and techniques, the present invention is a method to preserve the corneal stromal matrix of the cornea (i.e. Para. 11, item 3, above). The endothelium and epithelium is removed or rendered inactive, as neither is required according to the present invention and its applications. Thus, the focus of the present invention is the processing, packaging, sterilizing, and storing of non-viable, native corneal stromal matrix transplants and/or implants.